Optimization of a 50 MHz Frequency Modulated Continuous Wave radar system for the study of auroral E-region coherent backscatter

A 50 MHz Frequency Modulated Continuous Wave (FMCW) radar system, developed at the University of Saskatchewan to provide improved spatial and temporal resolution measurements of auroral E-region plasma processes, introduces ambiguous spectral information, due to spectral ghosting, for scattering events in which multiple radar echoes are detected. This thesis identifies two Linearly Frequency Modulated (LFM) radar waveforms used by the FMCW system as the source of the ghosting. An analysis procedure designed to counteract the spectral ghosting problem is developed but is not an ideal solution, and therefore replacement of the LFM waveforms is recommended. A detailed investigation of alternative radar waveforms using the Ambiguity Function and Ambiguity Diagram techniques is performed. A frequency coded continuous wave radar waveform based on a composite Costas sequence is proposed as a successor to the LFM waveforms. The composite Costas radar waveform will conserve the spatial and temporal resolutions extended by the LFM waveforms and preclude any spectral ghosting. Implementing the proposed radar waveform and avoiding receiver saturation issues with the mono-static FMCW radar system in which both the transmitting and receiving antenna arrays are simultaneously and continuously active and geographically co-located is also discussed. In addition to this, two 50 MHz backscatter events are presented in this thesis to demonstrate the effectiveness of the FMCW system, notwithstanding the spectral ghosting complication. The first event from November 21, 2009 is identified as a Type 1 instability and the second from September 13, 2009 is identified as a Type 2 instability which lasted for ~ 16 minutes. Linear plasma fluid theory is used to provide a brief interpretation of both scattering events

Accounting for dilution of SARS-CoV-2 in wastewater samples using physico-chemical markers

Most sewer networks collect domestic wastewater and a variable proportion of extraneous water, such as rainwater, through surface runoff and industrial discharges. Accounting for wastewater dilution is essential to properly quantify wastewater particle loads, whether these are molecular fragments of SARS-CoV-2, or other substances of interest such as illicit drugs or microplastics. This paper presents a novel method for obtaining real-time estimates of wastewater dilution and total daily volume through wastewater treatment works, namely when flow data is not available or unreliable. The approach considers the levels of several physico-chemical markers (ammonia, electrical conductivity, and orthophosphate) in the wastewater against their dry-weather levels. Using high-resolution data from the national Wastewater Surveillance Programme of Wales, we illustrate how the method is robust to spikes in markers and can recover peaks in wastewater flow measurements that may have been capped by hydraulic relief valves. We show the method proves effective in normalising SARS-CoV-2 viral loads in wastewater samples and discuss other applications for this method, looking at wastewater surveillance as a vital tool to monitor both human and environmental health

Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility.

Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.Support for the Netherlands Twin Register was obtained from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007); Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB; European Research Council (ERC-230374 and ERC-284167); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1). Part of the genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951). We acknowledge support from VU Amsterdam and the Institute for Health and Care Research (EMGO+). The Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). Dale R. Nyholt was supported by the Australian Research Council (ARC) Future Fellowship (FT0991022), NHMRC Research Fellowship (APP0613674) Schemes and by the Visiting Professors Programme (VPP) of the Royal Netherlands Academy of Arts and Sciences (KNAW). Allan F. McRae was supported by an NRMRC Career Development Fellowship (APP1083656). Grant W. Montgomery was supported by NIH grant (HD042157, a collaborative study of the genetics of DZ twinning) and NHMRC Fellowship (GNT1078399). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886), and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). We would like to thank also 23andMe's consented research participants for contributing data on age at menarche for the FSHB gene locus and the Twinning Gwas Consortium (TGC). Co-authors from: Finland (Anu Loukola, Juho Wedenoja, Emmi Tikkanen, Beenish Qaiser), Sweden (Nancy Pedersen, Andrea Ganna), United kingdom King's College London (Department of Twin Research & Genetic Epidemiology: Pirro Hysi, Massimo Mangino), Institute of Psychiatry, Psychology & Neuroscience, Medical Research Council Social, Genetic and Developmental Psychiatry Centre (Eva Krapohl, Andrew McMillan).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.ajhg.2016.03.00

Heliophysics and Amateur Radio:Citizen Science Collaborations for Atmospheric, Ionospheric, and Space Physics Research and Operations

The amateur radio community is a global, highly engaged, and technical community with an intense interest in space weather, its underlying physics, and how it impacts radio communications. The large-scale observational capabilities of distributed instrumentation fielded by amateur radio operators and radio science enthusiasts offers a tremendous opportunity to advance the fields of heliophysics, radio science, and space weather. Well-established amateur radio networks like the RBN, WSPRNet, and PSKReporter already provide rich, ever-growing, long-term data of bottomside ionospheric observations. Up-and-coming purpose-built citizen science networks, and their associated novel instruments, offer opportunities for citizen scientists, professional researchers, and industry to field networks for specific science questions and operational needs. Here, we discuss the scientific and technical capabilities of the global amateur radio community, review methods of collaboration between the amateur radio and professional scientific community, and review recent peer-reviewed studies that have made use of amateur radio data and methods. Finally, we present recommendations submitted to the U.S. National Academy of Science Decadal Survey for Solar and Space Physics (Heliophysics) 2024–2033 for using amateur radio to further advance heliophysics and for fostering deeper collaborations between the professional science and amateur radio communities. Technical recommendations include increasing support for distributed instrumentation fielded by amateur radio operators and citizen scientists, developing novel transmissions of RF signals that can be used in citizen science experiments, developing new amateur radio modes that simultaneously allow for communications and ionospheric sounding, and formally incorporating the amateur radio community and its observational assets into the Space Weather R2O2R framework. Collaborative recommendations include allocating resources for amateur radio citizen science research projects and activities, developing amateur radio research and educational activities in collaboration with leading organizations within the amateur radio community, facilitating communication and collegiality between professional researchers and amateurs, ensuring that proposed projects are of a mutual benefit to both the professional research and amateur radio communities, and working towards diverse, equitable, and inclusive communities

The History and Prehistory of Natural-Language Semantics

Contemporary natural-language semantics began with the assumption that the meaning of a sentence could be modeled by a single truth condition, or by an entity with a truth-condition. But with the recent explosion of dynamic semantics and pragmatics and of work on non- truth-conditional dimensions of linguistic meaning, we are now in the midst of a shift away from a truth-condition-centric view and toward the idea that a sentence’s meaning must be spelled out in terms of its various roles in conversation. This communicative turn in semantics raises historical questions: Why was truth-conditional semantics dominant in the first place, and why were the phenomena now driving the communicative turn initially ignored or misunderstood by truth-conditional semanticists? I offer a historical answer to both questions. The history of natural-language semantics—springing from the work of Donald Davidson and Richard Montague—began with a methodological toolkit that Frege, Tarski, Carnap, and others had created to better understand artificial languages. For them, the study of linguistic meaning was subservient to other explanatory goals in logic, philosophy, and the foundations of mathematics, and this subservience was reflected in the fact that they idealized away from all aspects of meaning that get in the way of a one-to-one correspondence between sentences and truth-conditions. The truth-conditional beginnings of natural- language semantics are best explained by the fact that, upon turning their attention to the empirical study of natural language, Davidson and Montague adopted the methodological toolkit assembled by Frege, Tarski, and Carnap and, along with it, their idealization away from non-truth-conditional semantic phenomena. But this pivot in explana- tory priorities toward natural language itself rendered the adoption of the truth-conditional idealization inappropriate. Lifting the truth-conditional idealization has forced semanticists to upend the conception of linguistic meaning that was originally embodied in their methodology

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.Peer reviewe

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes